Regional Intestinal Permeability in Dogs: Biopharmaceutical Aspects for Development of Oral Modified-Release Dosage Forms.

The development of oral modified-release (MR) dosage forms requires an active pharmaceutical ingredient (API) with a sufficiently high absorption rate in both the small and large intestine. Dogs are commonly used in preclinical evaluation of regional intestinal absorption and in the development of novel MR dosage forms. This study determined regional intestinal effective permeability (Peff) in dogs with the aim to improve regional Peff prediction in humans. Four model drugs, atenolol, enalaprilat, metoprolol, and ketoprofen, were intravenously and regionally dosed twice as a solution into the proximal small intestine (P-SI) and large intestine (LI) of three dogs with intestinal stomas. Based on plasma data from two separate study occasions for each dog, regional Peff values were calculated using a validated intestinal deconvolution method. The determined mean Peff values were 0.62, 0.14, 1.06, and 3.66 × 10(-4) cm/s in the P-SI, and 0.13, 0.02, 1.03, and 2.20 × 10(-4) cm/s in the LI, for atenolol, enalaprilat, metoprolol, and ketoprofen, respectively. The determined P-SI Peff values in dog were highly correlated (R(2) = 0.98) to the historically directly determined human jejunal Peff after a single-pass perfusion. The determined dog P-SI Peff values were also successfully implemented in GI-Sim to predict the risk for overestimation of LI absorption of low permeability drugs. We conclude that the dog intestinal stoma model is a useful preclinical tool for determination of regional intestinal permeability. Still, further studies are recommended to evaluate additional APIs, sources of variability, and formulation types, for more accurate determination of the dog model in the drug development process.

Pharmacokinetics and pharmacodynamics of enalapril and its active metabolite, enalaprilat, at four different doses in healthy horses.

Pharmacokinetic and pharmacodynamic of IV enalapril at 0.50 mg/kg, PO placebo and PO enalapril at three different doses (0.50, 1.00 and 2.00 mg/kg) were analyzed in 7 healthy horses. Serum concentrations of enalapril and enalaprilat were determined for pharmacokinetic analysis. Angiotensin-converting enzyme (ACE) activity, serum ureic nitrogen (SUN), creatinine and electrolytes were measured, and blood pressure was monitored for pharmacodynamic analysis. The elimination half-lives of enalapril and enalaprilat were 0.67 and 2.76 h respectively after IV enalapril. Enalapril concentrations after PO administrations were below the limit of quantification (10 ng/ml) in all horses and enalaprilat concentrations were below the limit of quantification in 4 of the 7 horses. Maximum mean ACE inhibitions from baseline were 88.38, 3.24, 21.69, 26.11 and 30.19% for IV enalapril at 0.50 mg/kg, placebo and PO enalapril at 0.50, 1.00 and 2.00 mg/kg, respectively. Blood pressures, SUN, creatinine and electrolytes remained unchanged during the experiments.

Intracoronary EnalaPrilat to Reduce MICROvascular Damage During Percutaneous Coronary Intervention (ProMicro) study.

OBJECTIVES: This study investigated the influence of intracoronary enalaprilat on coronary microvascular function and peri-procedural outcome measures in patients with stable angina undergoing percutaneous coronary intervention (PCI). BACKGROUND: Intracoronary angiotensin-converting enzyme inhibitors have been shown to relieve myocardial ischemia in stable patients and to improve epicardial flow in patients with ST-segment elevation myocardial infarction. Yet, it is still unclear whether these effects are mediated by a modulation of the coronary microcirculation. METHODS: We randomly assigned 40 patients to receive either an intracoronary bolus of enalaprilat (50 µg) or placebo before elective PCI. The index of microvascular resistance was measured at baseline, 10 minutes after study drug administration, and after PCI. High-sensitivity cardiac troponin T was measured as a marker of myocardial injury. RESULTS: Infusion of enalaprilat resulted in a significant reduction in index of microvascular resistance (27 ± 11 at baseline vs. 19 ± 9 after drug vs. 15 ± 8 after PCI), whereas a significant post-procedural increase in index of microvascular resistance levels was observed in the placebo group (24 ± 15 at baseline vs. 24 ± 15 after drug vs. 33 ± 19 after PCI). Index of microvascular resistance levels after PCI were significantly lower in the enalaprilat group (p < 0.001). Patients pre-treated with enalaprilat also showed lower peak values (mean: 21.7 ng/ml, range: 8.2 to 34.8 ng/ml vs. mean: 32.3 ng/ml, range: 12.6 to 65.2 ng/ml, p = 0.048) and peri-procedural increases of high-sensitivity cardiac troponin T (mean: 9.9 ng/ml, range: 2.7 to 19.0 ng/ml vs. mean: 26.6 ng/ml, range: 6.3 to 60.5 ng/ml, p = 0.025). CONCLUSIONS: Intracoronary enalaprilat improves coronary microvascular function and protects myocardium from procedure-related injury in patients with coronary artery disease undergoing PCI. Larger studies are warranted to investigate whether these effects of enalaprilat could result into a significant clinical benefit.

An integrated physiology-based model for the interaction of RAA system biomarkers with drugs.

The renin angiotensin aldosterone system (RAAS) is a paramount target for the pharmacological treatment of cardiovascular diseases. As modeling and simulation techniques are becoming increasingly utilized in cardiovascular research, our aim was to develop a physiology-based model that describes the effect of different drugs at different doses on the RAAS and integrates physiology-based description drug pharmacokinetics (PK). First, a basic RAAS model was developed in which equations for drug effects were included and missing parameters estimated. Next, a physiology-based PK model for enalapril and enalaprilat was developed and coupled to the RAAS model. Simulation of the effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aliskiren administration on angiotensins I and II did not reveal significant overestimation or underestimation. For all drugs, the error numerics were acceptable. The model also encompassed the PK of intravenous and oral enalapril and its conversion to enalaprilat. In summary, we report a physiology-based model for the interaction of the RAAS biomarkers angiotensin I and II with enalapril, benazepril, aliskiren, and losartan that allows for an adequate description of the RAAS response after single administration of the drugs. Such a comprehensive description may lead to a better understanding of the effects of pharmacological interventions in the RAAS.

Determination of enalapril and enalaprilat in small human serum quantities for pediatric trials by HPLC-tandem mass spectrometry.

The angiotensin converting enzyme-inhibitor enalapril is the prodrug of enalaprilat and used in the treatment pediatric hypertension and chronic heart failure. Pharmacokinetic data are lacking to provide adequate dosing and for pediatric pharmacotherapeutical trials it is imperative to minimize sample volume. Therefore an HPLC-tandem mass spectrometry (MS) method for the determination of enalapril and enalaprilat in 100 µL of human serum was developed and validated with benazepril as internal standard (IS). After solid-phase extraction, chromatography was performed on a Luna(®) RP-C(18) (2) column with methanol-water-formic acid (65:35:1, v/v/v) as mobile phase and a flow rate of 0.4 mL/min. The MS was set to positive-mode electrospray ionization and multiple reaction monitoring, analyzing the m/z transitions channels 377.3 → 234.2, 349.3 → 206.1 and 425.3 → 351.2 for enalapril, enalaprilat and IS. Calibration curves were linear in the range of 1.61-206 ng/mL (enalapril) and 1.84-236 ng/mL (enalaprilat) with coefficients of determination >0.99. Relative standard deviations of intra- and inter-run precisions were below 7% and relative errors were below 6 ± 7% for both analytes. Also stabilities were acceptable for both analytes. As an application example, concentrations of enalapril and enalaprilat in serum after oral administration of 20 mg enalapril maleat in a healthy volunteer were determined.

The effect of candesartan on the pharmacokinetics of enalaprilat in nephrotic rats.

BACKGROUND AND OBJECTIVES: The adverse reactions in combination of angiotensin-converting enzyme inhibitors (ACEIs) and Ang II receptor blockers (ARBs) were severer than that in monotherapy for patients with nephropathy. The effect of candesartan on pharmacokinetics of enalaprilat in nephrotic rats was investigated to make references for the clinical therapy in patients with nephropathy to avoid related adverse effects. MATERIALS AND METHODS: Nephrotic rats were prepared by adriamycin injection. Control group and one nephrotic group received enalapril alone, another nephrotic group received enalapril and candesartan simultaneously. Blood samples were drawn at time points after a single oral administration. The concentration of enalaprilat was determined using LC-MS/MS. RESULTS: Compared with control group and nephrotic group received enalapril alone respectively, Tmax of enalaprilat in nephrotic group received both enalapril and candesartan cilexetil prolonged about 21.43% and 6.224%, respectively; AUC(0-t) increased by 185.3% and 60.63%, respectively; Cmax increased by 219.4% and 56.64%, respectively; t1/2 increased by 163.7% and 30.05%, respectively; CL/F reduced by 65.12% and 40.78%, respectively. There were no significant differences of the V1/F of enalaprilat between three groups. The CL/F and t1/2 of enalaprilat showed significant correlations with serum creatinine (Scr) respectively (r = -0.7502; r = 0.5626). DISCUSSION: The combination with candesartan in nephrotic rats significantly changed the pharmacokinetics of enalaprilat, showing increased accumulation and decreased elimination. In view of these findings, we should lower dosage and prolong dosing interval for nephrotic patients in the combination of enalapril and candesartan.

Simultaneous quantification of enalapril and enalaprilat in human plasma by high-performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study.

A rapid, selective and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed to simultaneously determine enalapril and enalaprilat in human plasma. With benazepril as internal standard, sample pretreatment involved in a one-step protein precipitation (PPT) with methanol of 0.2 ml plasma. Analysis was performed on an Ultimate XB-C(18) column (50 mm x 2.1 mm, i.d., 3 microm) with mobile phase consisting of methanol-water-formic acid (62:38:0.2, v/v/v). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction-monitoring (MRM) mode via electrospray ionization (ESI) source. Each plasma sample was chromatographed within 2.5 min. The linear calibration curves for enalapril and enalaprilat were both obtained in the concentration range of 0.638-255 ng/ml (r(2) > or = 0.99) with the lower limit of quantification (LLOQ) of 0.638 ng/ml. The intra-day precision (R.S.D.) was below 7.2% and inter-day R.S.D. was less than 14%, while accuracy (relative error R.E.) was within +/-8.7 and +/-5.5%, determined from QC samples for enalapril and enalaprilat which corresponded to requirement of the guidance of FDA. The HPLC-MS/MS method herein described was fully validated and successfully applied to the pharmacokinetic study of enalapril maleate capsules in 20 healthy male volunteers after oral administration.

Pharmacokinetics and pharmacodynamics profiles of enalapril maleate in healthy volunteers following determination of enalapril and enalaprilat by two specific enzyme immunoassays.

BACKGROUND AND OBJECTIVES: Most of the pharmacokinetic (PK) parameters for enalapril and enalaprilat were established following determination of the drug and its metabolite, using angiotensin converting enzyme (ACE) inhibition assays. In these methods, enalapril has to be hydrolysed to enalaprilat first and then assayed. The purpose of this study was to re-estimate the PK parameters of enalapril and enalaprilat in healthy volunteers using two specific enzyme immunoassays for enalapril and enalaprilat. METHODS: The rate and extent of absorption of enalapril and enalaprilat from a 10-mg dose of two enalapril maleate commercial brands (Renetic and Enalapril) were estimated using a two-way-cross over design with 1-week washout period. Blood pressure was also measured at specified time intervals and correlated to enalaprilat plasma concentrations. RESULTS: For enalapril, the AUC(o-->infinity) values (Mean+/-SD) were 450.0+/-199.5 and 479.6+/-215.6 ng h/mL, Cmax values were 313.5+/-139.6 and 310.1+/-186.6 ng/mL, Tmax values were 1.06+/-0.30 h and 1.13+/-0.22 h, and t1/2 ranged between 0.3 to 6.1 h (1.6+/-1.5) and 0.40 to 5.05 h (1.3+/-1.0), for the two brands. For enalaprilat, the AUC(o-->infinity) values were 266.9+/-122.7 and 255.9+/-121.8 ng h/ml, Cmax values were 54.8+/-29.5 and 57.2+/-29.0 ng/mL, Tmax values were 4.6+/-1.6 h and 4.3+/-1.45 h, and t1/2 ranged between 1.1 to 10.5 h (4.5+/-2.9) and 0.6 to 9.4 h (3.5+/-2.5) for the two brands. CONCLUSIONS: Cmax values for enalapril are about 10 times those published in the literature and the rate and extent of absorption of the two brands of enalapril and their deesterification to enalaprilat following the administration of either brand were bioequivalent. Secondly, enalaprilat concentrations at 12-24 h following a single oral dose of enalapril in healthy volunteers were lower than those reported in the literature. The values reported here correlated with the return of blood pressure to predose level. Thirdly, enzyme immunoassays for enalapril and enalaprilat are better than ACE inhibition assays and can be used in bioequivalence assessment of enalapril and enalaprilat and for therapeutic drug monitoring in a clinical laboratory setting.

Gender differences in angiotensin-converting enzyme (ACE) activity and inhibition by enalaprilat in healthy volunteers.

This bioequivalence study was supported by Laboratorios Vita S.A (Barcelona). To study the existence of differences between sexes in the pharmacokinetic and pharmacodynamic of enalapril. A bioequivalence phase 1 clinical trial to compare two formulations of enalapril was carried out in twenty-four healthy volunteers (12 men and 12 women). Enalaprilat concentrations, plasma activity of ACE, and systolic and diastolic arterial pressure were determined. Basal activity of ACE and the maximum ACE inhibition were significantly smaller in women. No significant differences in the drug concentration required to produce 50% of Emax were observed. Women had lower systolic arterial pressures and ACE activities than men at any time, even when the maximum inhibition of the ACE activity was attained. Women at the follicular phase had a minimum activity of ACE significantly inferior than men. Healthy women had lower systolic arterial pressures and ACE activities than men.

Characterization of the pharmacokinetic and pharmacodynamic properties of the angiotensin-converting enzyme inhibitor, enalapril, in horses.

The pharmacokinetics of enalapril (0.5 mg/kg i.v.) and the pharmacodynamics of enalapril (0.5 mg/kg PO) in 5 mares were investigated. After single i.v. dosing, concentrations of enalapril and enalaprilat, its active metabolite, were measured. Two weeks later, enalapril was administered by nasogastric tube. Potassium, creatinine, blood urea nitrogen (BUN), enalapril, and enalaprilat concentrations and angiotensin converting enzyme (ACE) activity were measured in serum. In addition, heart rate, blood pressure, digital venous blood gases, and lactate were measured. Two weeks later, enalapril was again administered by nasogastric tube. To mimic activation of the renin-angiotensin-aldosterone system, angiotensin I (0.5 microg/kg) was administered at fixed intervals, followed by blood-pressure and heart-rate measurement. The elimination half lives of enalapril and enalaprilat were 0.59 and 1.25 hours, respectively, after i.v. administration. After PO administration, enalapril and enalaprilat were not detectable in serum. There was a tendency (P = .0625) toward a decrease in ACE activity 45-120 minutes after enalapril administration, but ACE activity suppression was never > 16%. There was a tendency (P = .0625) toward a decrease in mean arterial pressure (MAP) 6-8 hours after enalapril administration. Serum concentrations of potassium, creatinine, and BUN and digital venous blood gases and lactate concentrations did not change. In response to angiotensin I, there was a tendency (P = .0625) toward a decrease in the MAP response 4-24 hours after enalapril administration. Single-dose enalapril at 0.5 mg/kg PO did not demonstrate significant availability, pharmacodynamic effect, or substantial suppression of ACE activity.

Relative bioavailability study of 20-mg enalapril tablets in healthy male volunteers.

The pharmacokinetic and relative bioavailability studies of 20-mg enalapril tablets, the test product manufactured by Biolab, Thailand compared to the reference product (Merck Sharp & Dohme, USA) was conducted in 14 healthy Thai male volunteers following a single dose, two-period, crossover design. Each subject received 20-mg enalapril tablets of both formulations with a 1-week washout period. Plasma samples collected over a 24-h period after administration were analyzed by LC/MS/MS. Pharmacokinetic parameters were determined by using non-compartmental analysis. Regarding bioequivalence testing, the 90 per cent confidence intervals of Cmax and AUC(0-infinity) ratios (test/reference) of enalapril were 101.8-134.9 per cent and 105.9-121.4 per cent and those of enalaprilat were 104.2-122.3 per cent and 104.5-118.1 per cent. Based on the European bioequivalence guideline, the 90 per cent confidence intervals of Cmax and AUC(0-infinity) ratios of both parent and metabolite forms were within the acceptable ranges of 70-143 per cent and 80-125 per cent, respectively. It was concluded that the test formulation was bioequivalent to the reference formulation and both formulations can be used interchangeably in clinical practice.

Myocardial uptake and biochemical and hemodynamic effects of ACE inhibitors in humans.

There is little information on the processes affecting selective tissue ACE inhibition and the implications in human subjects. We compared intravenously administered ACE inhibitors, perindoprilat and enalaprilat, for myocardial drug uptake and effects on angiotensin and bradykinin peptides versus hemodynamic effects in 25 patients with stable angina and well-preserved left ventricular systolic function. Myocardial uptake was rapid and more efficient for perindoprilat than for enalaprilat (peak content at 26+/-3 and 30+/-4 seconds, 0.58+/-0.12% and 0.27+/-0.07% of the administered dose for perindoprilat and enalaprilat, respectively, P=0.04 for difference). Both drugs caused a decrease in angiotensin (Ang) II level, an increase in Ang I level, and reduction in Ang II/Ang I ratio in arterial and coronary sinus blood. Bradykinin (BK)-(1-9) and BK-(1-8) levels increased in arterial blood and BK-(1-8) levels increased in coronary sinus blood after drug administration. Perindoprilat and enalaprilat caused a small decrease in mean arterial pressure (-3+/-1%, P<0.05; and -4+/-1%, P<0.01, respectively) and LV+dP/dt (-5.8+/-1.7%, P<0.01 and -4.2+/-2.8%, P<0.05, respectively), whereas systemic vascular resistance index was unchanged. Despite relatively cardioselective uptake of perindoprilat, both drugs had similar effects on the cardiac metabolism of angiotensin and bradykinin and on cardiac function. Under resting conditions, both drugs exerted small negative inotropic effects.

Determination of enalapril and enalaprilat by enzyme linked immunosorbent assays: application to pharmacokinetic and pharmacodynamic analysis.

We have developed two enzyme linked immunosorbent assay (ELISA) methods for determining enalapril and enalaprilat in plasma. In this study, 48 healthy subjects received an oral dose of either 10 or 20 mg of enalapril and plasma concentrations of enalapril and enalaprilat were determined by their specific ELISA methods. These plasma concentrations and blood pressure measurements were applied to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of both enalapril and enalaprilat. The enalapril values for the area under the curve (AUC(0)--> infinity ) were 480 +/- 216 and 832 +/- 325 ngh/mL, maximum plasma concentrations (C(max)) were 310 +/- 187 and 481 +/- 185 ng/mL, and times required to reach the maximum concentration t(max) were 1.13 +/- 0.22 and 1.09 +/- 0.33 h for 10 and 20 mg doses, respectively. The enalaprilat values for AUC(0)--> infinity were 256 +/- 122 and 383 +/- 158 ngh/mL, C(max) values were 57 +/- 29 and 72.9 +/- 33.6 ng/mL and t(max) values were 4.28 +/- 1.45 and 4.05 +/- 01.22 h for 10 and 20 mg doses, respectively. The C(max) values of enalapril were approximately 10 times higher than those in the literature, which were determined by angiotensin converting enzyme (ACE) inhibition assays following alkaline hydrolysis, but similar to those of enalaprilat. The PD profiles revealed a significant correlation between enalaprilat concentrations in plasma and the decrease in systolic and diastolic blood pressures (r = -0.95 with P < 0.001 and r = -0.95 with P < 0.001), respectively, following a single oral dose of enalapril. These ELISA methods have the advantage of being simple, accurate, sensitive, and do not depend on enalaprilat binding to ACE. Such methods can be used for analysis and kinetic testing of enalapril and enalaprilat in biological fluids.

Comparative study of effects of angiotensin II receptor antagonist, KD3-671, and angiotensin converting enzyme inhibitor, enalaprilat, on cough reflex in guinea pig.

Angiotensin converting enzyme (ACE) inhibitor prevents the inactivation of bradykinin by inhibiting ACE activity, leading to side effects such as dry cough and angioedema. KD3-671 is a novel nonpeptide angiotensin II antagonist which is expected to exhibit persistent hypotensive action without these side effects. In this study, we investigated the relationship between the pharmacokinetics and cough-inducing effect of this drug in guinea-pig, compared with that of an ACE inhibitor, enalaprilat. KD3-671 was not significantly different from the vehicle treatment in the ability to induce coughing, whereas enalaprilat significantly enhanced coughing compared with the vehicle treatment. Thus, as expected from its mechanism of pharmacological action, KD3-671 did not induce coughing. We suggest that the citric acid-induced guinea pig coughing model will be useful in preclinical studies to examine the effect of drug on pulmonary function.

High serum enalaprilat in chronic renal failure.

BACKGROUND: Most angiotensin-converting enzyme (ACE) inhibitors and their metabolites are excreted renally and doses should hence be reduced in renal insufficiency. We studied whether the dosage of enalapril in daily clinical practice is associated with drug accumulation of enalaprilat in chronic renal failure. METHODS: Fifty nine out-patients with plasma creatinine >150 micromol/L and chronic antihypertensive treatment with enalapril were investigated, in a cross-sectional design. RESULTS: Median glomerular filtration rate (GFR) was 23(range 6-60) ml/minute/1.73 m2. The daily dose of enalapril was 10 (2.5-20) mg and the trough serum concentration of enalaprilat was 31.8 (<2.5-584.7)ng/ml. Ninety percent of the patients had higher serum concentrations of enalaprilat than has been reported in subjects with normal kidney function, and a marked elevation of serum enalaprilat was observed in patients with GFR <30 ml/minute. All but three patients had serum ACE activity below the reference range. The ACE genotype did not influence the results. Additional pharmacokinetic studies were done in nine patients in whom GFR was 23 (10-42)ml/minute/1.73 m2. The median clearance of enalaprilat was 28 (16-68) ml/minute and correlated linearly with GFR (r=0.86, p=0.003). Intra-subject day-to-day variation in trough concentrations was 19.7%. CONCLUSION: Patients with chronic renal failure given small or moderately high doses of enalapril may thus have markedly elevated levels of serum enalaprilat. Whether this affords extra renoprotection, or on the contrary may inappropriately impair renal function, is not known, and should be investigated in prospective, controlled studies.

Dissociation between ACE activity and autonomic response to ACE inhibition in patients with heart failure.

BACKGROUND: Administration of angiotensin-converting enzyme (ACE) inhibitors to patients with congestive heart failure has been shown to increase parasympathetic tone as indicated by increases in high-frequency heart rate variability. The mechanism for this effect, including its relation to changes in baroreflex activity, blood pressure variability, and suppression of ACE activity, remains undefined. This study was designed to test the relation of these variables, which may govern changes in autonomic activity, to the previously described increase in parasympathetic tone. METHODS: Seven patients with heart failure received a 3-hour infusion of the ACE inhibitor enalaprilat. Hemodynamic variables and parameters of heart rate and blood pressure variability, baroreflex gain derived from the interaction of heart rate and blood pressure variability, and serum ACE activity were measured during and after the infusion. Measures of heart rate and blood pressure variability were also compared against a historic control group. RESULTS: Serum ACE activity was significantly suppressed throughout and after enalaprilat infusion. Hemodynamic measures did not change other than a small decline in right atrial and pulmonary capillary wedge pressures. Parasympathetic tone showed an initial significant increase with a peak at 2 hours but then declined below baseline 8 hours after initiation of enalaprilat infusion. Sympathetically influenced low-frequency heart rate variability was significantly increased above baseline in the enalaprilat treatment group 8 hours after initiation of the infusion. Baroreflex gain showed a significant trend to an increase with the maximum value coinciding with the peak in parasympathetic tone. There was no change in blood pressure variability in the enalaprilat group and no change in baroreflex gain, heart rate variability, or blood pressure variability in the control group. CONCLUSIONS: Parasympathetic tone and baroreflex gain increased with parenteral administration of an ACE inhibitor but subsequently decreased below baseline values despite continued suppression of serum ACE activity. The dissociation between ACE suppression and autonomic response to ACE inhibition indicates that enzyme systems not reflected by plasma ACE activity or independent from the classic pathways of angiotensin formation contribute to the regulation of the autonomic response to ACE inhibition in patients with heart failure. The absence of significant change in hemodynamic variables or in blood pressure variability indicates that these autonomic changes are not an indirect reflex response to ACE inhibitor-induced vasodilation or hemodynamic baroreceptor stimulation.

Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency.

AIMS: To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril. METHODS: Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance

Evaluation of hypotonic preswelling method for encapsulation of enalaprilat in intact human erythrocytes.

The hypotonic preswelling method for encapsulation of drugs in intact human erythrocytes was evaluated using enalaprilat as a model peptide-like drug. Several process variables, including volume, concentration, pH, and method of addition of drug solution, type of erythrocyte-suspending medium, temperature, initial packed density of erythrocytes, and individual process steps, were exploited with respect to their effects on the loading parameters (i.e., loaded amount, efficiency of entrapment, and cell recovery). In addition, the probable mechanism by which the erythrocytes were loaded by enalaprilat at the point of lysis was shown to be a simple concentration gradient-based diffusion through membrane openings occurring on hemolysis. Finally, the adopted method was validated, and the results showed a considerable degree of reproducibility and recovery for the entire loading procedure.

Pharmacokinetic studies of enalaprilat in the in vitro perfused human placental lobule system.

The objectives of this study were to evaluate the transplacental kinetics and effects on placental function of the angiotensin converting enzyme (ACE) inhibitor, enalaprilat, in the dually perfused human placental lobule system. When placed in the maternal perfusate at a high therapeutic serum concentration (150 ng/ml), enalaprilat was rapidly transferred from the maternal perfusate into placental tissue followed by a gradual release from the placenta into the fetal perfusate. Cmax and AUC values for enalaprilat in the maternal perfusate were approximately 3 times higher than in the fetal perfusate, and drug levels did not equilibrate between maternal and fetal perfusates during the 4-6 hours of perfusion. The more highly perfused regions of the placental lobule had higher drug levels than non-perfused areas. At the end of the perfusion period, the mean percent of total drug added in the maternal perfusate was 59%, with 23% in the fetal perfusate and the remainder (18%) in placental tissue. Despite the relatively high levels of drug found in placental tissue, there were no alterations in placental function as measured by fetal volume loss, fetal pressure, glucose utilization, lactate production, hCG release, net fetal oxygen transfer, and oxygen consumption. Results from this study clearly document placental transfer of enalaprilat in the perfused human placental lobule system. The lack of effect on placental function suggests that enalaprilat has no direct effect on fetoplacental vascular beds, and that fetal hypotension occurring from ACE inhibitor exposure may be due to direct effects on the fetal kidney and not to decreased perfusion of fetoplacental vascular beds; these findings require further validation in an in vivo model.

Treatment of congestive heart failure: experience with fosinopril.

The prevalence of congestive heart failure (CHF), a debilitating condition associated with impaired quality of life and markedly shortened life expectancy, is increasing. The goals of therapy for CHF are reducing symptoms, improving functional capacity, and slowing the progression of the condition. In most cases, this is best achieved with a combination of diuretic and vasodilator therapy. Angiotensin-converting enzyme (ACE) inhibitors have several advantages over other vasodilatory agents and are becoming widely used for treating CHF. The most recently introduced ACE inhibitor, fosinopril, is at least as effective as enalapril, and its dual and compensatory route of excretion is particularly advantageous in patients with renal insufficiency. Fosinopril may also have particular benefits in the prevention of CHF, as it has beneficial effects on cardiac function that may help delay the onset of overt cardiac failure.